The ability to orally administer peptide or peptide-like therapeutic agents has been a long-standing goal of pharmaceutical research. For example, many efforts have been made to develop an oral dosage form for insulin. Unfortunately, these efforts have been unsuccessful.
Properties which make peptides difficult to administer orally include their susceptibility to enzymatic degradation in the digestive tract and the fact that peptides are not readily transported from the digestive system into the blood stream. As a result of these problems, it is difficult to achieve desired blood levels of peptides or peptide-like therapeutic agents with relatively low oral doses and a relatively low number of oral doses per day.
Methods used to overcome the ability of peptides to be enzymatically degraded and to improve absorption into the blood stream from the digestive tract have included making analogs which are less peptide-like in structure and which are reduced in size (i.e., molecular weight). Such methods are deemed to be successful when the peptide analog achieves satisfactory blood levels after oral administration.
The above-mentioned techniques have been applied to preparing analogs of the peptide substrate of the enzyme renin. Small, peptide-like molecules have been prepared which show efficacy in lowering blood pressure. For example, compound I (shown below) reduces blood pressure in salt depleted dogs after oral or intravenous administration. However, the bioavailability on oral dosing (to fasted dogs) of the dihydrochloride salt of compound I as a powder filled capsule is about 17-30% and as a tablet is about 40%. To be able to administer the compound at the lowest possible does and lowest frequency of dosing, it would be preferrable if the oral bioavailability of compound I and its pharmaceutically acceptable salts was higher than that exhibited by a conventional solid dosage form. ##STR2##